Firefly Mice and Pancreas Regeneration

Almost all cases of Type I diabetes are currently treated with the same method: insulin. Because of an immune response that attacks the insulin-producing cells of the pancreas, diabetics must replace the endogenous hormone from external sources to process sugar and maintain safe blood glucose levels. Except for a tiny minority of cases where a genetic mutation is found to explain their disease, insulin injections become an unpleasant daily ritual for Type I diabetics that they will need for their entire lives.

But scientists and clinicians hope to someday offer diabetics more permanent ways of managing, or even erasing their disease. Transplantation of pancreatic islets – which contain beta cells, the insulin factories of the pancreas – have achieved very limited success, offering the recipient temporary glucose control. But finding compatible donors is difficult, the patient must continuously take immunosuppressive drugs, and even with therapy, 90 percent of those transplants fail within five years.

In 2003, an even better solution was proposed: what if a diabetic could simply regenerate their own damaged pancreatic beta cells? A team from Massachusetts General Hospital announced that mice were capable of pancreatic cell regeneration when the overactive immune response was controlled alongside an injection of spleen cells. Several groups, including one from the University of Chicago, recreated the study, and while they failed to replicate the effectiveness of spleen cells, a promising degree of beta-cell regeneration was observed.

“I think it was a little bit controversial for a long time. Most people felt that when you lost the beta cells, they were pretty much gone. But recently it became clear that, at least in mice, there is a pretty substantial regeneration by some groups,” said Anita Chong, professor of surgery at the University of Chicago Medical Center. “If the observation in mouse could be translated into humans, this would be very significant.”

So Chong’s group continued to study regeneration, looking for specific treatments or protocols that would maximize the recovery of beta cells. Yet the studies were laborious, with time-intensive data collection requiring 20-30 hours of microscope work for each mouse in a given study.

“We realized that the standard way of looking at beta cell regeneration was extremely tedious and subjective,” Chong said.

A workaround for that laboratory annoyance was inspired by an unlikely source: the firefly. The laboratory of Graeme Bell, professor of medicine and human genetics, developed a transgenic mouse with the enzyme luciferase (responsible for the firefly’s distinctive glow) attached to the insulin promoter. So cells that produce insulin will also produce luciferase, and when an activating luciferin salt is injected, they glow. While imperceptible to the naked eye, the mouse can be placed in a photon-counting detector that allows researchers to quickly assess the amount of pancreatic beta cells present.

Those mice were then used for a regeneration study published earlier this year in the journal PLoS One. The hypothesis, according to first author and surgical resident Eric Grossman, was to test whether merely controlling glucose levels in a mouse model of diabetes would help pancreatic beta cells to regenerate. Half the mice received an islet cell transplant, while the other half were simply treated with insulin via an implantable pellet.

“We felt that it was clinically applicable if, with tight glycemic control of appropriate management of our surrogate for diabetes, you see recovery of beta cell function,” Grossman said. “If you were to extrapolate it to humans, better control of your glycemia would encourage pancreatic beta cell regeneration.”

Both conditions worked – repeated measurements using their new bioluminescent mice showed that beta cells gradually grew back after both islet cell transplant and insulin treatment. Even when the islet cells or insulin implants were removed, stable blood glucose was sustained, suggesting recovery of the native pancreatic beta cells.

“The result in glycemic control after removing the transplanted islets is indicative of restoration of beta cell function in the native pancreas,” Grossman said. “This model for transplant is simply a model to deliver insulin in a temporary fashion and then remove it.”

That result alone does not contain the answers for attempting similar beta cell regeneration in humans, Chong cautioned. After all, millions of diabetics have controlled blood sugar via insulin treatment for decades and not experienced the spontaneous regeneration of beta cells, she pointed out. But the new, improved glowing mouse model allows her laboratory to test different co-treatments – immunosuppresive drugs or growth factors – that might make a pancreatic restart possible in human patients, or would at least make current islet cell transplant procedures more successful and durable.

“This is hopefully going to be the model upon which multiple years of experiments are going to be occurring,” Chong said. “I think endogenous regeneration has a long way to go. So the intermediate step might be if we can make islet transplantation a little bit better for this subset of patients as a sort of a baby step. That would be actually pretty good.”